Cx46 mRNA expression was also linked with improved survival in ER positive patients which, however, was preserved also in ER negative patients, suggesting a reciprocal regulation of Cx46 compared to Cx43 expression in this subgroup. This is in line with data gained in lens cell cultures showing the simultaneous down-regulation of Cx43 and upregulation of Cx46 expression by the tumor promoter phorbol ester or by the activation of the MAPK/ERK pathway. Differential regulation of connexin isotypes are rather common and allows connexins to serve either as conditional tumor suppressors in primary cancer or tumor supporters in advanced, metastatic cases. Examples in gynecological tumors include the re-expression of Cx26 induced by phorbol ester and its down-regulation via PR, which induce the opposite effects on Cx43. Also, 17b estradiol promotes Cx43 expression and function but reduces Cx26 and Cx32 production and Reversine activities. The cytoplasmic connexin protein we detected in breast cancers can be compatible with the potential channel independent functions of connexins observed in malignant tumors. Tight correlations were found between mRNA and protein expression and relatively coherent links between these and breast cancer prognosis for connexin subtypes which were either localized to the myoepithelial layer only or both to myoepithelial and luminal epithelial cells in normal mammary glands, as opposed to the luminal epithelia related Cx26 and Cx32, which showed partly discordant prognostic links. This suggests that connexin expression in myoepithelia is more consistently regulated than in luminal cells at least in a malignant tumor setting. Accordingly, in line with mRNA data, elevated Cx43 and Cx30 protein levels were linked with better and poorer RFS, respectively, in the whole patient cohort. Most significantly, differential connexin expression allowed the prognostic stratification of grade 2 patients into good or poor RFS subgroups by is situ testing of Cx43 levels; or grade 3 patients into poor or good OS subgroups by monitoring Cx30 levels. Potential prognostic relevance of connexins was indirectly supported by the positive statistical link of Cx43 protein levels with ER positivity and its negative link with tumor grade and by the positive link between Cx30 protein levels and mitotic index. As a contrary, Cx26 linked with worse outcome in luminal B patients at the transcript level, was associated with better RFS in the whole cohort and in ER positive patents at the protein level. Also, though Cx32 expression was linked with improved RFS at the transcript level, it showed an inverse prognostic link at the protein level in most breast cancer subgroups. Because of the close correlations between the results of independent mRNA array platforms and the validated specificity of the connexin antibodies used by western blots, the discordant prognostic links between mRNA and protein levels may not be associated with defective probes or techniques. Besides transcription factors and epigenetic processes, post-transcriptional pathways can also be involved in the regulation of connexins in breast cancer, which may more significantly affect Cx26 and Cx32 than other isotypes.